May 27, 2009 — (San Francisco, California) Women veterans are 2 to 3 times more likely to commit suicide than nonveteran women. Furthermore, female veterans are more likely to be young and use firearms to commit suicide compared with their civilian counterparts, who tend to choose other methods — commonly drug overdose.
Presented here at the American Psychiatric Association 162nd Annual Meeting, 2 studies — a small longitudinal study and a much larger, cross-sectional study — show that suicide risk is high among this growing population.
"The relative risk, especially in the longitudinal study, was quite high — 3-fold is a very high relative risk in epidemiology, and that finding was surprising to many of us," study investigator Bentson McFarland, MD, PhD, from Oregon Health and Science University, in Portland, told Medscape Psychiatry.
A Growing Concern
Dr. Bentson McFarland
Suicide in this population, said Dr. McFarland, is a growing concern. The number of women in the United States military has increased dramatically in the past number of years, and women now make up roughly 10% to 15% of active service members; the numbers of women veterans in the United States is approaching 2 million.
"Previous studies have suggested that male veterans are at more than twice the risk of suicide compared with nonveteran males. We wanted to look at women who have been in the military to see if they were also at elevated risk," Dr. McFarland told conference attendees.
A 2007 longitudinal study of women veterans, the investigators revealed, which followed individuals for a period of 12 years, suggested that women who have been in the military had a 3-fold increased risk for suicide compared with nonmilitary women. Data for this study came from the National Health Interview Study and was then linked with data from the National Death Index.
It is important to note, said Dr. McFarland, that this study was population-based and therefore the findings are generalizable to all military personnel and not just those in the Veterans Affairs (VA) health system.
He pointed out that research conducted by the Department of Veterans Affairs in 2001 revealed that the vast majority of veterans (76.6%) receive all of their healthcare services outside of the VA system.
While male veterans had a 2-fold increased risk for suicide compared with nonveteran males, the study revealed that women had a more than 3-fold increased risk (HR, 3.62) compared with nonmilitary women.
However, said Dr. McFarland the numbers were small and included 11 suicides among female veterans and 246 in nonveteran females.
Nevertheless, with this strong signal of increased suicide risk, the investigators set out to determine whether the findings could be replicated in a large, cross-sectional, population-based study.
Young Women at Greatest Risk
For the second study, the researchers used data from the Centers for Disease Control and Prevention National Violent Death Reporting System. This database was started in 2003 and aggregates information from death certificates and coroner/medical-examiner data from 17 participating states.
The information provided also includes a direct question about whether individuals have ever served in the military, as well as substantial information about the decedents, including cause of death.
The study results revealed that from 2003 to 2006 there were 171 female veteran suicide cases vs 5174 nonveteran female suicides. A total of 75 (44%) women veterans shot themselves, and 96 (56%) died by other methods. In contrast, 33% of nonveteran women died by firearms. The odds ratio for suicide for female veterans vs other women was 1.79.
In addition, suicide among nonveteran women was greatest between the ages of 35 and 64 years. In contrast, the peak age for suicide among military women was much younger — between 18 and 34 years.
"Women veterans are at about 79% greater risk of suicide than nonveteran women, and this risk varies markedly by age. The bottom line for clinicians is that even if you are outside the Veterans Affairs system, you will be seeing veterans in your practice, and some of them will be women who may well be at elevated risk of suicide," said Dr. McFarland.
"Clinicians should ask their female patients about military service and also inquire about low mood and difficulty with sleep or appetite, as well as problems with substance abuse, thoughts about suicide, and access to firearms," he added.
The study was supported by the National Institute of Mental Health and the American Foundation for Suicide Prevention Distinguished Investigator Award.
American Psychiatric Association 162nd Annual Meeting: Abstract SCR 21-61. Presented May 20, 2009.
Caroline Cassels is the news editor for Medscape Psychiatry. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke Foundation of Canada's Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at CCassels@webmd.net.
Caroline Cassels Caroline Cassels is the news editor for Medscape Psychiatry. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke Foundation of Canada's Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at CCassels@webmd.net.
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May 22, 2009 (London, United Kingdom) — Blood-pressure-lowering drugs should be offered to everyone, regardless of their blood pressure level, as a safeguard against coronary heart disease and stroke, researchers who conducted a meta-analysis of 147 randomized trials (comprising 958 000 people) conclude in the May 19 issue of BMJ [1].
“Guidelines on the use of blood-pressure-lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure,” write DrsMalcolmRLaw and NicholasWald (Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, UK). “Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.”
“Whatever your blood pressure, you benefit from lowering it further,” Law told heartwire. “Everyone benefits from taking blood-pressure-lowering drugs. There is no one who does not benefit because their blood pressure is so-called normal.”
Six years ago, Law and Wald advocated the use of a polypill--containing a statin, three blood-pressure-lowering drugs (each at half the standard dose), folic acid, and aspirin--which they maintained could prevent heart attacks and stroke if taken by everyone 55 years and older and by everyone with existing cardiovascular disease [2].
In the current meta-analysis, which included people aged 60 to 69, they singled out blood-pressure-lowering drugs to determine the quantitative efficacy of different classes of antihypertensive agents in preventing coronary heart disease (CHD) and stroke. They also sought to determine who should receive treatment.
All Antihypertensives Prevent CHD and Stroke
Overall, the results of the meta-analysis showed that in people aged 60 to 69 with a diastolic blood pressure before treatment of 90 mm Hg or a systolic blood pressure of 150 mm Hg, three drugs at half standard dose in combination (as in the polypill) reduced the risk of CHD by approximately 46% and of stroke by 62%. However, when used individually, a single antihypertensive agent at standard dose had about half this effect.
The five main classes of blood-pressure-lowering drugs--thiazides, beta blockers, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, and calcium-channel blockers--were similarly effective in preventing CHD events and strokes, with the exception of calcium-channel blockers, which had a greater preventive effect on stroke than the other four agents (relative risk, 0.92; 95% confidence interval, 0.85 to 0.98).
People with and without cardiovascular disease derived equal benefit, with similar percentage reductions in CHD events and stroke, and regardless of what their blood pressure was before treatment. Even patients with blood pressures considered to be low--110 mm Hg systolic and 70 mm Hg diastolic--showed fewer CHD events and a reduced incidence of stroke when taking an antihypertensive.
Law and Wald also report that calcium-channel blockers reduced the incidence of heart failure by 19%, and that the other antihypertensive agents reduced heart failure by 24%.
In an accompanying editorial [3], DrRichardMcManus (University of Birmingham, UK) and Dr Jonathan Mant (University of Cambridge, UK) write that the findings of Law and Wald will contribute to debate on the management of hypertension in several areas. “Taken at face value, these findings provide tacit support for the use of a ‘polypill’ to lower the risk of cardiovascular disease in people likely to be at high risk (such as all people over the age of 55) without first checking their blood pressure.”
In a comment to heartwire, McManus added that he believes that the findings reinforce the view that treatment to lower blood pressure should be offered on the basis of risk, regardless of blood pressure.
Throwing the Baby Out With the Bath Water
On the other side of the Atlantic, hypertension experts were not so sanguine in their opinion of Law and Wald’s conclusions.
Commenting on this study for heartwire, DrJamesElliott (Rush Medical College, Chicago, IL) said he took issue with the authors’ suggestion that the measuring of blood pressure was unnecessary.
“Professors Wald and Law made the revolutionary comment some years ago that we should abandon blood pressure and simply treat everyone at high CVD risk with their magic polypill, which they claimed reduced heart disease and stroke by 90%.This meta-analysis is an unusual compilation of data that supports that hypothesis.”
Abandoning blood pressure measuring is like throwing the baby out with the bath water, Elliott said.
Elliott also took issue with the meta-analysis, which he called “old-fashioned.”
“I think Wald and Law have become the ultimate lumpers. They have included the 37 studies where beta blockers were used against placebo in people with heart attacks, and they have lumped those in with all the other kinds of therapies that we use to lower blood pressure and prevent other events. Nobody, as far as I can remember, has ever included that set of 37 trials in with the other antihypertensive trials because it represents such a different population. They have done the old-fashioned, simple meta-analysis. But there are better ways to understand the data.”
A Meta-Analysis Is Like a Sausage
Adding his opinion, DrFranzMesserli (St Luke’s-Roosevelt Hospital Center, New York City) said that by including 147 trials in their meta-analysis, the authors had to make numerous assumptions, “some possibly valid, others clearly not.”
Because the “blood pressure fall was not reported in patients with a history of coronary heart disease, they estimated this fall from a meta-analysis of blood pressure trials. This is clearly inappropriate since the fall in blood pressure depends on the pretreatment level, and patients with coronary heart disease who often are hypotensive (particularly post MI) will not respond the same way as do patients with hypertension,” he told heartwire.
It is little surprise that beta blockers now, all of a sudden, look better than in any other review ever done, Messerli added. “Numerous meta-analyses have clearly demonstrated that beta blockers do not reduce the risk of coronary heart disease in hypertension, despite the fact that they lower blood pressure. Thus, despite its appearance of being bigger and better, this study is yet another example of my dictum: A meta-analysis is like a sausage, only God and the butcher know what goes in it and neither would ever eat any.”
Law and Wald disclosed that they hold patents (granted and pending) on the formulation of a combined pill to simultaneously reduce four cardiovascular risk factors, including blood pressure. McManus disclosed that he has a financial relationship with Sanofi-Aventis, Pfizer, A.Menarini Pharma, and Merck Sharp & Dohme. Elliott and Messerli have disclosed no relevant financial conflicts of interest.
The risk for death after AF ablation is 1 in 1000 patients or 1 in 1385 procedures.
Catheter ablation is an accepted procedure for patients with atrial fibrillation in whom medical treatment is ineffective. Currently, the only indication for AF ablation is impaired quality of life (QOL); ablation is not recommended for patients without symptoms who merely wish to stop taking warfarin. Individuals with AF have an increased mortality risk, and no AF treatment, including ablation, has been shown to reduce that risk. The AF ablation procedure itself carries a variety of risks. However, the incidence of death from complications of AF ablation has not been determined, because the data are from single-center or small multicenter trials.
In this international survey of 162 centers, 32,569 patients underwent 45,115 AF ablation procedures. In all, 32 deaths occurred (0.98 per 1000 patients; 0.71 per 1000 procedures), including 7 from tamponade, 5 from atrioesophageal fistula, and 3 from stroke.
Comment: As noted in an accompanying editorial, these data provide useful guidance to physicians and patients regarding the risks of AF ablation. Whether a 1-in-1385 procedural mortality risk is justified by potentially improved QOL is an individual patient decision. However, to put this risk in perspective, it is roughly the equivalent of the risk of knee replacement — another invasive QOL-improving procedure — and it is much lower than the risk of elective coronary percutaneous interventions, arguably also performed largely to improve QOL.
A New Antipsychotic for Exacerbations of Schizophrenia?
Paliperidone might be no better than other second-generation antipsychotics.
With generic risperidone now approved, new trials of paliperidone, its proprietary offspring, were expected. This 6-week, randomized, controlled, double-blind, international study was industry-sponsored, -designed, and -reported. The 399 participants had chronic schizophrenia (mean illness duration, 10 years) and a recent exacerbation requiring rehospitalization. Patients with treatment-resistant disease were excluded.
One day after discontinuing other psychiatric medications, patients began extended-release paliperidone at 6 mg/day, quetiapine at 50 mg/day, or placebo. Target doses, achieved by day 5, were at the high end of recommended ranges (paliperidone, 9 mg/day; quetiapine, 600 mg/day); higher doses were optional. In the first 2 weeks, patients received monotherapy (except as needed for agitation or insomnia); during the following 4 weeks (additive phase), other medications could be added. The study’s primary endpoint was change in Positive and Negative Syndrome Scale (PANSS) total scores at week 2. Results were significantly better with paliperidone than with quetiapine at week 2.
During the additive phase, further PANSS changes were similar in the paliperidone and quetiapine groups. In intent-to-treat analyses, paliperidone was superior to quetiapine. Similar percentages of patients in the paliperidone and quetiapine groups took additional antipsychotics or other psychiatric medications (53%–55%). Mean prolactin levels were significantly higher with paliperidone than with quetiapine or placebo.
Comment: Skeptical readers will wonder about this study’s design and analysis. Why was quetiapine selected as the comparator (instead of olanzapine or haloperidol)? Was the study’s playing field level? Quetiapine requires 5 days to reach target doses, but paliperidone is often clinically effective at 3 days; it is not surprising that paliperidone separated from placebo at day 5 but quetiapine did not separate until day 9. Also, why are significance tests discussed when results favor paliperidone, but not when they might favor quetiapine (e.g., prolactin levels)? We need to be wary of industry-sponsored clinical trials showing benefit for the sponsor’s product (Am J Psychiatry 2006; 163:185).
Fall in congenital heart defects after folic acid fortification introduced
19 May 2009
MedWire News: The birth prevalence of severe congenital heart defects in Canada fell significantly after the introduction of a public health measure to fortify grain with folic acid, a study shows.
The findings support the hypothesis that folic acid has a preventive effect on heart defects, say the authors.
Louise Pilote (McGill University, Montreal, Canada) and colleagues analyzed Quebec administrative databases to establish the annual birth prevalence of severe congenital heart defects (tetralogy of Fallot, endocardial cushion defects, univentricular hearts, truncus arteriosus, or transposition complexes) in the period 1990 to 2005.
Fortification of grain products has been mandatory in Canada since December 1998, the researchers explain, but the impact on birth heart defects at the population level has not previously been examined.
Writing in an advance online publication by the British Medical Journal, they report that 2083 infants were born with severe congenital heart defects out of a total of 1,324,440 births during the whole study period. This corresponded to an average birth prevalence of 1.57 per 1000 births.
Time trend analysis showed that there was no change in the birth prevalence of congenital heart defects in the 9 years before folic acid fortification, at a rate ratio of 1.008. But the 7-year period after the introduction of mandatory fortification of flour and pasta with folic acid was accompanied by a 6.2% decrease per year in birth prevalence, at a rate ratio of 0.938.
Further analysis showed a significant (p<0.001) interaction between the time period (before/after fortification) and calendar year, “suggesting that the decreasing trend after the flour fortification did not occur by chance,” Pilote and co-authors note.
The change in time trend was seen for both conotruncal and non-conotruncal defects analyzed separately.
The researchers conclude that future studies are needed to address the impact of folic acid fortification on the incidence of congenital heart defects and its long-term effects, as well as to determine the optimal level of folic acid intake required to achieve a reduction in the birth prevalence.
Association Between PPIs and Spontaneous Bacterial Peritonitis
Patients with SBP were more likely to have used PPIs than were patients without SBP.
Lately, proton-pump inhibitor (PPI) use has attracted considerable attention for some possible untoward consequences, including excess risk for several conditions (pneumonia, Clostridium difficile-associated disease, and fractures) and lowered efficacy of concurrent clopidogrel. Now, a retrospective case-control study suggests an association with spontaneous bacterial peritonitis (SBP) in hospitalized patients with cirrhosis and ascites.
Seventy patients with SBP were matched by age and Child’s class to 70 patients without SBP. The prevalence of prehospital use of PPIs was much higher in the SBP group than in the control group (69% vs. 31%). Significantly heightened risk with PPI use persisted in multivariate analysis (odds ratio for association between PPI use and SBP, 4.3). Chart reviews suggested that half the patients who received PPIs (in either group) had no indication for these drugs.
Comment: The difference in PPI use between patients with and without SBP was striking in this study. A proposed mechanism is that, by weakening the acid barrier to gastrointestinal colonization by orally ingested bacteria, PPIs abet bacterial overgrowth, translocation of bacteria across the intestinal wall, bacteremia, and seeding of ascitic fluid. Although case-control studies don’t establish cause and effect, limiting use of PPIs to valid indications makes sense in all patients, including those with cirrhosis and ascites.
Two-thirds of Americans are obese or overweight, and the Centers for Disease Control has declared that obesity is at epidemic proportions in the United States.[1] Obesity is a risk factor for many diseases, such as diabetes mellitus, hypertension, stroke, and heart and renal disease. Despite this relationship, obese people with these diseases live longer than their normal-weight counterparts. This conundrum has been called the "obesity paradox."[2] But before you postpone your diet or have that extra jelly donut, let's examine the data.
The Obesity Paradox is best studied in congestive heart failure, showing that obese patients have a better prognosis than leaner ones.[3-8] Of note, none of the congestive heart failure trials have found obesity to worsen the prognosis.
The obesity paradox has also been described for other diseases, including coronary artery disease, hypertension, and stroke, and in dialysis patients.[9,10] Cachexia from advanced disease was at first thought to be the explanation. These findings, however, show a continuous dose-response reduction in mortality across a gradation of body mass index levels. And in many of these studies, the lowest body mass index was calculated to have a healthy percentage of body fat and not at levels consistent with a malnourished state.
How do we explain the obesity paradox? In short, the answer is unknown, but there are several possibilities. First, obese patients may present earlier with less disease burden. Second, obese patients may be more aggressively treated. Third, adipose tissue may secrete protective cytokines and other hormonal products. Finally, these findings are associative, but do not prove a cause-and-effect relationship.
So can we have our cake and eat it too? Based on the data at hand, it is likely that the obesity paradox is a real association, but what it means for the recommendations and treatment of our patients is food for thought.
That's my opinion. I'm Dr. George Griffing, Professor of Medicine at St Louis University and Editor-in-Chief for Internal Medicine at eMedicine.
The use of omega-3 fatty acids and other supplements as opposed to a healthy diet to prevent cardiovascular disease is controversial and the effects beyond current drugs are disputed. There has always been a tendency in medicine to take a lifestyle-related risk protective factor and try to bottle it for convenience and commercial advantage. The most famous instance is the vast use of anti-oxidant vitamins as opposed to eating fruit and vegetables which are known to be associated with reduced rates of cardiovascular disease.[1,2]
In contrast to a proper diet, anti-oxidant vitamin supplements show no benefit in large-scale randomised placebo-controlled trials.[3] This, however, has not stopped the classical techniques of public relations and news management being applied to protect a multibillion dollar market.
Deny the story.
Allege bias – ‘the trial was not representative’.
Quibble on details – ‘inadequate methods, duff statistics, inclusion of flawed trials etc’.
Shift the goalposts – ‘the trial would work in a subpopulation’.
Use anecdotal reports – ‘use basic science mechanistic studies; post hoc analyses’.
If all else fails admit the truth but only when convenient.
Gradually both doctors and patients are slowly beginning to believe that anti-oxidant vitamins are of no use. So they switch to a new panacea as they still wish to believe. This new cure-all for cardiovascular disease is omega-3 fatty acids and particularly those derived from fish; a belief based on the Eskimo (Inuit) diet.[4] So what is the evidence?
First of all, omega-3 (n-3) fatty acids are a heterogeneous group of molecules which are poorly synthesised in man.[5] The common forms include docosahexaenoic acid (DHA) (22:6; n-3) and eicosapentaenoic acid (EPA) (20:6; n-3) which are often contrasted to omega-6 (n-6) fatty acids which include γ-linolenic (18:3; n-6) and the polysubstrate for inflammatory mediators-arachidonic acid (20:4; n-6).[6,7] Omega-3 fatty acids are found in plants and in fish but as many plants also contain high levels of omega-6 fatty acids fish consumption is recommended as a primary source. Omega-3 fatty acids are supposed to exert their beneficial effects through reducing sympathetic overactivity, enhancing nitric oxide-mediated vasodilation, reducing monocyte adhesion and reducing levels of arachidonic acid-derived mediators including thromboxane A2 as well as reducing thrombomodulin and von Willebrand factor and to also reduce insulin resistance probably through actions at the peroxisomal proliferator-activating receptor (PPAR)-gamma.[5,8,9] The PPAR effects may also be responsible for their action in reducing triglycerides but they are multiple gene activators affecting PPAR-α, PPAR-γ and PPAR-δ but also farnesoid-X receptors, Liver-X receptor and hepatic nuclear factor (HNF)-4α.[5,10] The prime action seems to be PPAR-α with secondary actions on PPAR-γ after conversion through 15-lipoxygenase. They reduce hepatic lipogenesis by downregulating sterol receptor element-binding protein 1c, upregulation of hepatic and muscle fatty acid oxidation via PPARs and an increase in glycogen synthesis by reducing HNF-4α. There is increasing evidence that DHA and EPA may have differential effects and thus considering all omega-3 fatty acids to be similar may be an over-simplification.[11,12]
Numerous observational studies have documented an inverse relationship between questionnaire-assessed omega-3 fatty acid concentrations allied on a few occasions with measurement of membrane and tissue concentrations with reduced rates of cardiovascular disease.[13–16] The common recommended intake is 25–60 g of fish high in omega-3 fatty acids or one portion of such fish weekly or monthly. Yet other sources of omega-3 are almost equally beneficial – nuts, soybean oil being associated with 30–60% reductions in cardiovascular disease.[15] Overall fatal coronary heart disease (CHD) is reduced by 38% (18–54%) stroke by 31% (12–46%) with high as opposed to low fish intake being associated with a 17% (10–24%) reduction in fatal myocardial infarction (MI) and 14% (8–19%) reduction in any CHD. One meta-analysis shows that omega-3 fatty acid consumption is associated with a 23% reduction in mortality and 32% in cardiovascular mortality – similar to statins.[17–19] However, when reviewed in detail the studies are less clear. Prospective studies show unclear results with some positive [e.g. the Diet And Reinfarction Trial (DART)[20]] and some negative [Dietary Angina Reduction Trial (DART-2)[21,22]]. Another meta-analysis of dietary fish intake in 15,806 patients in 11 trials suggested a 17% (8–25%) reduction in CHD mortality and 25% (22–29%) reduction in non-fatal MI with some as opposed to no fish intake in people without pre-existing CHD.[17] A further meta-analysis of 11 studies and 13 cohorts comprising 222,364 patients over 11.2 years found a 11% (+1% to 21%) reduction in CHD mortality with increased benefit at higher intakes (> 5/week) with a 38% (18–54%) reduction with fish consumption five times per week.[14] Only five studies could be assessed for non-fatal MI and these showed no consistent benefit with fish intake. The relationship between fish consumption and risk reduction was complex in another analysis with the suggestion of a partial plateau in effect with 1–2 portions of oily fish per week.[16] In primary prevention each extra serving per week reduced risk by 4%.[16] Yet, this same analysis was limited in patients with pre-existing disease as all the trials used commercial supplements at large doses. One potential problem with a high fish intake is a parallel increase in mercury exposure which may itself predispose to CHD but no consistent effect has been seen in epidemiological studies examining the role of mercury exposure.[16]
The data for stroke is based on a meta-analysis of nine cohorts which shows a 9% (-6% to 21%) reduction in stroke for any as opposed to no fish consumption with a weak dose proportional effect increasing to 31% (12–46%) reduction in those consuming fish > 5/week.[23] Yet other studies only suggest a 2% increment with extra portions.[24] Yet as these analyses mention higher fish intake is associated with higher social class, more exercise, less smoking and less obesity and so the dietary studies may not be unconfounded.
The data for α-linolenic acid (ALA), the precursor to DHA or EPA are weaker.[25] A number of flax oil trials were confounded by changes in protocols, short durations, small size. The best known is the Lyon Heart Health study where a 5% (1.8 g) ALA-enriched diet given in an open randomised fashion to 605 patients post-MI resulted in a 73% (31–88%) reduction at 2 years in cardiac death and non-fatal MI which was maintained to 4 years.[26] Yet even this trial was confounded by parallel changes in saturated fat, fish and anti-oxidant intakes.
The argument for supplementation is driven by the results of the Grupo Italiano per lo Studio della Sopravvivenza nell'Infarcto miocardio – prevenzione (GISSI-P) study[27] which is the largest study in the field. In this study, 11,324 patients with recent myocardial infarcts (< p =" 0.048)" p =" 0.053)" p =" 0.02;" nnt =" 157/year)" p =" 0.008;" nnt =" 159/year)">
More recently, the Japan EPA Lipid Intervention Study (JELIS)[28] investigated the effect of 1.8 g EPA added to new background 10–20 mg pravastatin or 5–10 mg simvastatin in 18,645 patients at least 6 months post-MI with total cholesterol > 6.5 (LDL-C > 4.4 mmol/l). The primary end-point was cardiovascular death, fatal and non-fatal MI and stroke, and percutaneous coronary intervention. The design assumed event rates of 2.13% per year in secondary prevention (n = 3664) and 0.58% per year in primary prevention (n = 14,981). Unusually for international trials but similar to MEGA[29] the study recruited 69% women. Statin therapy was effective in reducing LDL-C by 25% in both groups to 3.25 mmol/l. The overall results showed a 19% (5–31%) reduction in events (3.5% → 2.8%; p = 0.01; NNT = 658/year). At 4.6 years there was a non-significant 18% (+6% to 37%) reduction in the primary prevention group (1.7% → 1.4%; p = 0.11; NNT = 1538/year) while events were reduced by 19% (0–34%) in the secondary prevention group (10.7% → 8.7%; p = 0.048; NNT = 375/year). There was no inter-group heterogeneity, but it is noticeable that as in MEGA the greatest event rate and degree of reduction was seen in men were events were reduced by 24% (6–38%) while women showed a non-significant 13% (+13% to 32%) reduction in events. The event reduction was driven by a 24% reduction in unstable angina in the whole cohort comprising reduced angina in the secondary prevention group and in fatal and non-fatal MI and angina in the primary prevention group.
There is little data on the role of omega-3 fatty acids in peripheral arterial disease.[30] One meta-analysis exist of six studies with 313 patients comparing omega-3 fatty acid supplementation with placebo lasting up to 2 years. No significant differences were seen in ankle brachial pressure index, pain-free or maximal walking distance. Blood viscosity levels decreased. As in other studies gastrointestinal side effects were observed and LDL-C levels were increased by 0.80 mmol/l (0.34–1.26 mmol/l).
Omega-3 fatty acids have anti-arrhythmic effects in animal models and cell culture.[31] They have negative chronotropic and inotropic effects on cardiomyocytes by affecting sodium- and calcium-channel function and secondary effects on cytosolic-free calcium levels.[32] Recently a number of trials have examined their effects in cardiac arrhythmias. In small-scale studies of patients undergoing bypass grafting omega-3 fatty acids were associated with a 68% (2–90%) reduction in new atrial fibrillation in an uncontrolled study of 160 patients.[33] In contrast in a study of 200 patients with implanted cardiac ventricular defibrillators (ICDs) 2-year therapy showed an increase in ventricular tachycardia (VT) at 2 years but patients were not taking class I or class III anti-arrhythmics and had a high rate of activation.[34] More recently, the Study on Omega-3 Fatty acid and ventricular Arrhythmia[35] randomised 546 patients with low fish intakes and with an ICD and > 1 episode of ventricular arrhythmia within the last year to 2 g of fish oil (900 mg EPA) as opposed to corn oil for 12 months. There was no difference in the primary end-point of death, VT or ventricular fibrillation (VF) although a trend (p = 0.09) was seen to reduced rates in the small subgroup of patients with prior myocardial infarcts. In the Fatty Acid Arrhythmia Trial[36] 402 patients with an ICD were randomised to 2.6 g of omega-3 fatty acids or olive oil. At 12 months there was borderline 28% reduction in new VT or VF (p = 0.057). However, 35% of patients discontinued the treatment and a per protocol analysis suggested a 38% (p = 0.03) reduction in new arrhythmias. However, it can be seen that these studies are unlikely to be adequately powered to draw unequivocal conclusions about the role of omega-3 fatty acids in VF.
On the basis of GISSI-P omega-3 fatty acid supplements are recommended in many guidelines[37,38] and in the UK NICE guidelines if <>[39] However, the main benefit with omega-3 fatty acids occurred early prior to major statin initiation.[27] It is notable that in GISSI-P there seemed to be a reduction in acute coronary syndromes and arrhythmias in the first 6 months.[40] In JELIS, the bulk of the benefits seem to occur after 2.5 years but although statin therapy was universal, it was systematically under-dosed by modern guidelines, and unfortunately there was no acute initiation of omega-3 supplements to allow a comparison with the results achieved earlier in GISSI-P. The question that remains is what would be the effect of omega-3 fatty acids added to optimal statin therapy in a high-risk group? Basic calculation suggest that if statins are used as in the Treatment to new Targets study[41] or other dose comparison studies then the NNT will rise to 480/year (i.e. 97 for a typical 5-year period) which is of borderline utility for health economic purposes.
There remains a need for further studies of adequate size, rigorous design and utilising optimal background therapy. The OMEGA trial because of report in 2008 has randomised 3800 patients within 2–5 days of MI to 1 g DHA–EPA or placebo with a primary end-point of sudden cardiac death at 1 year.[42] The GISSI – heart failure study is examining the role of statin and or 1 g DHA–EPA in 7000 patients with heart failure in a 2 × 2 design using a primary end-point of total mortality and hospital admission.[43] In patients with diabetes the ASCEND trial,[44] 10,000 patients are being randomised to 1 g DHA–EPA or aspirin in a 2 × 2 design to investigate the effects of omega-3 fatty acids on major adverse cardiac events. The results are expected in 2012.
So what can one conclude? There seems to be a clear benefit for a diet or the lifestyle associated with eating fish. The data on supplements is confusing and does not necessarily show clear benefits when added to optimal-lipid management with statins which definitely reduce cardiovascular events[45] and may themselves have some anti-arrhythmic effects.[46] So the recipe for a healthy life is fish but no chips. And may be some (red) wine.
May 12, 2009 — New observational evidence supports previous evidence from a randomized controlled trial that folic acid–containing supplements lower the risk for pregnancies affected by neural tube defects, according to a US Preventive Services Task Force (USPSTF) statement and review of evidence reported in the May 5 issue of the Annals of Internal Medicine. The review suggests that the previously noted association of folic acid use with twin gestation may be confounded by fertility interventions.
Based on the evidence, the USPSTF has issued a grade A recommendation that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 - 800 µg) of folic acid.
Regarding benefits of this preventive measure, the USPSTF found convincing evidence that taking supplements containing 0.4 to 0.8 mg (400 - 800 µg) of folic acid during the periconceptional period lowers the risk for neural tube defects. Regarding potential harms, adequate evidence suggests that folic acid from supplementation at usual doses is not associated with serious harms.
For women who are planning or are capable of pregnancy, the USPSTF therefore concludes that there is high certainty that the net benefit of folic acid supplementation during pregnancy is substantial.
Tracy Wolff, MD, MPH, and colleagues from the USPSTF write, "Neural tube defects (NTDs) are among the most common birth defects in the United States,...In 1996, the...USPSTF recommended that all women planning a pregnancy or capable of conception take a supplement containing folic acid to reduce the risk for NTDs."
USPSTF Review Process
The goal of the review was to provide a basis for an updated USPSTF recommendation by searching for new evidence published since 1996 regarding the benefits and harms of folic acid supplementation for women of childbearing age, with the aim of preventing neural tube defects in offspring. The reviewers searched MEDLINE and Cochrane Central Register of Controlled Trials from January 1995 through December 2008, as well as recent systematic reviews and bibliographies cited in identified articles. Experts were also contacted for any pertinent suggestions.
Inclusion criteria for the studies were English-language articles describing the benefits and harms of folic acid supplementation in women of childbearing age to reduce neural tube defects in offspring. These included randomized controlled trials, cohort studies, case-control studies, systematic reviews, and meta-analyses. The investigators reviewed, abstracted, and rated the identified studies for methodologic quality using predefined USPSTF criteria.
The reviewers identified 4 observational studies that showed a benefit of reduction of the risk for neural tube defects associated with use of folic acid–containing supplements. However, a summary of the reduction in risk could not be calculated because of differences in study type and methods. There was only 1 included study on harms, which reported that the apparent association of twin pregnancies with folic acid intake disappeared after adjusting for in vitro fertilization and underreporting of folic acid intake.
Limitations of the review include studies with limited evidence on dose. Also, none of the studies that discussed B12 supported or refuted the potential harm of masking vitamin B12 deficiency in women of childbearing potential. The review did not provide a comprehensive review of the effects of folic acid on all possible outcomes or of the effects of dietary intake of folic acid.
Furthermore, the review did not include a comprehensive picture of how folic acid–containing supplements may prevent other congenital abnormalities, consideration of the evidence on counseling to increase dietary intake of folic acid, or comparison of the effect of folic acid on neural tube defects among different ethnic groups or among groups with genetic differences that may affect folic acid metabolism.
"New observational evidence supports previous evidence from a randomized, controlled trial that folic acid–containing supplements reduce the risk for NTD-affected pregnancies," the review authors write. "The association of folic acid use with twin gestation may be confounded by fertility interventions."
Updates to 1996 Recommendation
The accompanying USPSTF statement is an update of the 1996 USPSTF recommendation that all women planning or capable of pregnancy take a multivitamin supplement containing folic acid to prevent neural tube defects. The statement is based on the evidence regarding folic acid supplementation in women of childbearing age published since the 1996 USPSTF recommendation, without review of evidence regarding food fortification with folic acid, counseling to increase dietary intake, or screening for neural tube defects.
"Approximately 1 in every 1000 pregnancies is affected by a neural tube defect," write USPSTF chair Ned Calonge, MD, MPH, from the Colorado Department of Public Health and Environment in Denver, and colleagues. "Although a personal or family history of a pregnancy affected by a neural tube defect is associated with an increased risk for having an affected pregnancy, most cases occur in the absence of any positive history."
Recommendations From Other Associations
This USPSTF recommendation is consistent with published guidelines of other specialty professional organizations. In 2003, the American College of Obstetrics and Gynecology recommended periconceptual use of a multivitamin supplement containing 0.4 mg of folic acid for most women of childbearing potential.
The American Academy of Family Physicians strongly recommends prescribing folic acid supplementation of 0.4 to 0.8 mg/day for women planning to become pregnant and without a history of neural tube defects, and 0.4 mg/day of folate supplementation to women of childbearing age who are not planning pregnancy.
"The American College of Obstetrics and Gynecology, AAFP [American Academy of Family Physicians], and most other organizations recommend 4 mg/d for women with a history of neural tube defects," the statement authors conclude.
"The American Academy of Pediatrics endorses the U.S. Public Health Service recommendation that all women capable of becoming pregnant consume 400 mcg of folic acid daily to prevent neural tube defects,' particularly for adolescent, ''sexually active women who do not plan to use effective contraception or abstain from sexual intercourse.' Because of teratogenesis and impaired folate metabolism associated with certain antiepileptic drugs, the American Academy of Neurology recommends folic acid supplementation of no less than 0.4 mg/d for women of childbearing age with epilepsy."
May 11, 2009 — Early research suggests that low folate levels may be linked to an increased risk for allergy and asthma, but more study is needed to confirm the association.
Researchers from the Johns Hopkins Children's Center examined the blood folate levels of more than 8,000 people with and without asthma and allergies who were enrolled in a large, national health registry.
They found that those with the lowest serum folate levels were 31% more likely to have test-verified allergy and 40% more likely to have wheeze than people with the highest levels. They also found them 16% more likely to have diagnosed asthma, although the asthma finding wasn't statistically significant.
Pediatric allergist and study researcher Elizabeth C. Matsui, MD, MHS, tells WebMD that the relationship appeared to be dose-dependent, meaning that the people with the highest blood folate levels had the lowest incidence of wheeze and allergies and the people with the lowest folate levels had the highest incidence.
But she warns that it is too soon to recommend that people take folic acid -- the synthetic form of folate used in supplements -- in an effort to reduce their risk for allergy and asthma or to treat symptoms.
"That would be premature," she says. "Our findings are a clear indication that folic acid may indeed help regulate immune response to allergens, and may reduce allergy and asthma symptoms. But we still need to figure out the exact mechanism behind it, and to do so we need studies to follow people receiving treatment with folic acid."
Few Are Folate Deficient
Less than 5% of Americans have so little folate in their blood that they are considered deficient in the B vitamin, Matsui says.
That's because since 1996, the U.S. government has required folic acid to be added to cereals, flours, pastas, rice, and other grain products in an effort to ensure that pregnant women get enough of the vitamin to protect against certain birth defects.
Folate is also abundant in leafy green vegetables like spinach and turnip greens, citrus fruits, dried beans, liver, and many other foods.
The people in the study who had the least folate in their blood were not deficient in the vitamin. Instead, they had what would be considered low-normal plasma folate levels, Matsui says.
Nevertheless, even after adjusting for known risk factors for asthma and allergy, people with the lowest blood folate levels had the highest odds of test-verified allergy, wheeze, and allergy-related IgE antibodies.
The study appears in the latest online issue of the Journal of Allergy & Clinical Immunology.
Allergies, Asthma, and Folic Acid
Allergist Cascya Charlot, MD, tells WebMD that the findings are intriguing enough to justify interventional studies that could determine if folic acid supplementation really does protect against asthma and allergies.
Charlot is medical director of Allergy and Asthma Care of Brooklyn.
"There may be something there," she says. "Now we need to see if treating people with folic acid will reduce symptoms."
The study is among the first to suggest that folic acid may protect against allergy and asthma, but several other studies -- also preliminary -- suggest that supplementation may promote allergic disease in some populations.
Last October, Duke University researchers reported that mice exposed to high levels of folate prior to birth had an increased risk for allergic disease early in life.
The researchers suggested that the dramatic increase in asthma over the last two decades may be at least partly related to efforts to increase supplementation among pregnant women.
Charlot says the seemingly conflicting findings highlight the need for more research.
"It looks like there is something here, but it is clear that we don't really understand what is going on," she says.
Is Donepezil Effective for Mild Cognitive Impairment?
Donepezil was not more effective than placebo, according to the study’s primary endpoint.
A substantial proportion of patients with the amnestic (memory-impairment) subtype of mild cognitive impairment (MCI) eventually progresses to Alzheimer disease. In this industry-sponsored study, researchers examined the effect of donepezil — approved for use in Alzheimer disease but not MCI — in 821 patients with amnestic MCI.
Patients were randomized to 48-week courses of donepezil or placebo. The investigators specified that donepezil would not be considered superior to placebo unless it was favored in scores on both of two primary endpoints (the ADAS-cog, which evaluates cognition, and the CDR-SB, which evaluates cognition and function).
At 48 weeks, mean ADAS-cog scores were significantly improved in the donepezil group compared with the placebo group, but the difference was only 1 point on an 89-point scale. CDR-SB scores did not differ in the two groups. For eight secondary endpoints (representing various other standardized assessment tools), two favored donepezil and six did not differ between groups. Adverse events possibly or probably related to treatment were significantly more common with donepezil than with placebo (47% vs. 25%).
Comment: In this study, donepezil was not superior to placebo, according to the primary efficacy endpoint selected by the researchers. Clinicians should not prescribe donepezil for patients with mild cognitive impairment.
PLoS Medicine: Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill?
Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill?
Leonie Callaway1,2, Paul B. Colditz2,3, Nicholas M. Fisk2,3*
1 School of Medicine, The University of Queensland, Brisbane, Queensland, Australia, 2 Royal Brisbane & Women's Hospital, Herston, Queensland, Australia, 3 University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia
Citation: Callaway L, Colditz PB, Fisk NM (2009) Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill? PLoS Med 6(5): e1000077. doi:10.1371/journal.pmed.1000077
Funding: The authors received no specific funding for this article.
Competing interests: LC declares that she has no competing interests related to this Perspective. PBC was involved with the Micronutrient Initiative in lobbying for flour fortification in Australia and New Zealand. NMF was a member of the UK Advisory Board of Ferring Pharmaceuticals until 2007, has received recent travel funds from Ferring International, the Royal College of Obstetricians and Gynaecologists, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and the North American Fetal Treatment Network, and acts as an expert witness in medicolegal litigation in obstetrics. Between 1996–2002, he was a member of a UK lobby group (chair Prof. N. Wald) to enrich commercial flour to prevent spina bifida.
Provenance: Commissioned; not externally peer reviewed
Linked Research Article
This Perspective discusses the following new study published in PLoS Medicine:
Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, et al. (2009) Preconceptional folate supplementation and the risk of spontaneous preterm birth: A cohort study. PLoS Med 6(5): e1000061. doi:10.1371/journal.pmed.1000061
In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth.
Preterm birth is increasing, and complicates 12% of deliveries in the United States. It is the dominant cause of neonatal mortality. Preterm birth also accounts for one in three children with vision impairment, one in five with mental retardation, and almost half with cerebral palsy [1]. Babies born weighing under 2,500 g are at heightened risk in adulthood of diabetes and cardiovascular disease [1]. These short- and long-term sequelae make the prevention of preterm birth a public health priority.
Although some preterm births are indicated for maternal or fetal complications, most are spontaneous. Yet there is no licensed tocolytic agent available in the US to treat early-onset contractions, no treatment for threatened preterm labor that improves neonatal outcome, and no new class of drug under development [2]. In the face of such therapeutic nihilism, attention has turned instead to prophylaxis. There is encouraging evidence that prophylactic progesterone in women at increased risk (shortened cervix, previous history) reduces the incidence of very preterm birth [3],[4]. Enthusiasm for this approach has been dampened by two setbacks. First, progesterone does not work in all pregnancies at risk of preterm labor (specifically twins). Second, 17-hydroxyprogesterone caproate recently failed to win approval from the US Food and Drug Administration due to safety concerns about fetal death rates in monkeys and humans [5],[6].
Prophylactic Folic Acid: Newfound Benefit of an Old Approach? Top
Poor periconceptional nutrition is implicated in idiopathic preterm labor in both animal models and human studies. As with the progesterone story, there is renewed interest in decades-old suggestions that folic acid may reduce preterm birth [7]–[9]. Because of poor compliance with recommendations to take periconceptional folate supplements to prevent neural tube defects (NTDs), more than 50 countries have already introduced mandatory wheat flour fortification [10]–[12]. In California, this was associated with a modest reduction in low birthweight and preterm birth [13].
In this issue of PLoS Medicine, Radek Bukowski and colleagues report that additional voluntary folic acid supplementation was associated with a major reduction in very preterm births, those most at risk of adverse outcomes [14]. Women taking supplements for at least one year before conception had a 70% reduction in spontaneous preterm birth between 20–28 weeks, and a 50% reduction between 28–32 weeks, when compared to those with no additional supplementation. Long-term compared to no supplementation was associated with a reduction in the risk of spontaneous preterm birth before 32 weeks from one in 154 to one in 423.
Given the multiple causes of preterm labor, is this degree of hazard reduction plausible [15]? Biologically, the authors point to anti-inflammatory mechanisms. On the one hand, infection is implicated in only a minority of preterm births, but on the other, infection is found increasingly at earlier gestational ages, such as those suggested to benefit most in this study. In keeping with this mechanism, no association was seen with non-infective phenomena, such as indicated preterm birth or disorders of placentation.
Methodologically, the study has several strengths, and is unlikely to be replicated. It is based on a huge dataset, with prospective recording of dietary supplements and potential confounders, and gestational age determined accurately on first trimester ultrasound. Those born preterm because of intervention were appropriately censored.
Nevertheless, there remains need for caution. This was a secondary analysis of a Down syndrome screening study, and so information on folic acid dose, formulation (with or without other supplements), and daily compliance is incomplete. In relation to numerators, there were only 16 births at under 32 weeks in those on long-term supplements. One unanswered question is whether women on folic acid for at least one year took a larger dose more diligently, resulting in higher folate levels at conception compared to women taking shorter-term supplements (women taking supplements were better educated, white, non-smoking, and different to the remaining women on nearly every measured parameter). Indeed, controlling for confounders negated the significance of any effect of less than one year's supplementation. Long-term consumption of preconceptional folic acid supplements in other countries might suggest a subfertility/planned pregnancy effect, but Bukowski's study occurred against the backdrop not only of mandatory flour fortification, but also recommendations in the US that all women of childbearing age, not just those planning pregnancy, consume daily 0.4 mg of folate over and above that in a natural diet [11].
These tantalizing findings add further impetus to the study of preconceptional factors and interventions that impact on duration of pregnancy. The ultimate evidence as to whether folic acid prevents spontaneous preterm birth will require a randomized controlled trial, but conducting such a trial may prove challenging on several fronts. First, there are robust reasons to encourage all women to take folic acid. Second, one third of the world already has mandatory folic acid fortification [11]. Third are the ethical difficulties with a control group, although these might be surmounted in geographical areas where prepregnancy supplementation is not yet supported. One practical way forward would be a randomized controlled trial of ongoing folic acid supplementation in mothers with a previous very preterm birth, ideally with high-dose and low-dose arms compared to standard care to dissect out dose versus duration effects.
There is increasing evidence that recommended supplementation levels are inadequate to optimize pregnancy outcome. Studies from North and South America show that low-level fortification of flour prevents at most only 40% of NTDs, because such fortification provides only a quarter of the recommended daily intake [16],[17]. Bukowski and colleagues' study confirms that fewer than 20% of women follow recommendations for additional folate, while in settings without mandatory fortification of flour, such as most of Europe, as few as 5% of women take the recommended 400 µg dose in the three months prior to conception [10]. Higher daily doses result in higher folate levels, and there is a continuous dose–response relationship between early pregnancy folate levels and NTD prevention [18]. Compelling arguments have been made to increase mandatory flour fortification levels 2–4 fold and pre-pregnancy folic acid tablets to 4–5 mg per day, aiming to prevent around 85% of NTDs [17]. There is little downside, now that earlier concerns about folic acid unmasking vitamin B12 deficiency appear resolved, and the evidence on whether folate supplementation increases twinning remains inconclusive [19],[20].
Does Bukowski and colleagues' study provide additional impetus for an increase in the recommended dose of folic acid [19]? No, that would be premature in the absence of intervention studies to substantiate folic acid reducing very preterm birth. This is particularly important given the experience with cardiovascular disease, where epidemiological evidence suggested protective effects of folic acid supplementation that were not borne out in subsequent randomized trials [21]. In the interim, super-supplementation can be justified entirely on the basis that it would double the number of NTDs prevented.
Spong CY (2009) Preterm birth: An enigma and a priority. Obstet Gynecol 113: 770–771. Find this article online
Fisk NM, Atun R (2008) Market failure and the poverty of new drugs in maternal health. PLoS Med 5: e22. doi:10.1371/journal.pmed.0050022.
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Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, et al. (2009) Preconceptional folate supplementation and the risk of spontaneous preterm birth: A cohort study. PLoS Med 6: e1000061. doi:10.1371/journal.pmed.1000061.
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